US9440966B2 - Compounds for treatment of metabolic syndrome - Google Patents

Compounds for treatment of metabolic syndrome Download PDF

Info

Publication number
US9440966B2
US9440966B2 US14/007,868 US201214007868A US9440966B2 US 9440966 B2 US9440966 B2 US 9440966B2 US 201214007868 A US201214007868 A US 201214007868A US 9440966 B2 US9440966 B2 US 9440966B2
Authority
US
United States
Prior art keywords
compound
mmol
compounds
hours
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
US14/007,868
Other languages
English (en)
Other versions
US20150051204A1 (en
Inventor
Juan Carlos AGREDA NAVAJAS
Roberto Mikio Kassuya
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SJT MOLECULAR RESEARCH SL
Original Assignee
SJT MOLECULAR RESEARCH SL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SJT MOLECULAR RESEARCH SL filed Critical SJT MOLECULAR RESEARCH SL
Priority to US14/007,868 priority Critical patent/US9440966B2/en
Assigned to SJT MOLECULAR RESEARCH, S.L. reassignment SJT MOLECULAR RESEARCH, S.L. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MIKIO KASSUYA, ROBERTO, AGREDA NAVAJAS, JUAN CARLOS
Publication of US20150051204A1 publication Critical patent/US20150051204A1/en
Application granted granted Critical
Publication of US9440966B2 publication Critical patent/US9440966B2/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A23L1/293—
    • A23L1/30—
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A23L33/165—Complexes or chelates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/30—Dietetic or nutritional methods, e.g. for losing weight
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/69—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing fluorine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/06—Preparations for care of the skin for countering cellulitis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/326—Foods, ingredients or supplements having a functional effect on health having effect on cardiovascular health
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/3262—Foods, ingredients or supplements having a functional effect on health having an effect on blood cholesterol
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/328—Foods, ingredients or supplements having a functional effect on health having effect on glycaemic control and diabetes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/332—Promoters of weight control and weight loss
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/92—Oral administration

Definitions

  • the present invention refers to new ⁇ -carbolinic compounds and its use for the treatment of metabolic diseases such as metabolic syndrome, type I and II diabetes.
  • ⁇ -carbolinics compounds comprises a class of indol alkaloids, natural and synthetic, that present a wide range of important biological and pharmacological properties, such as antimicrobial and antiviral activities, action on metabolism and as powerful antitumorigenic agents (1, 2).
  • Several researches have been developed for obtaining ⁇ -carbolinic alkaloid derivatives, with different replacements in 1, 3 and 9 positions of the ⁇ -carbolinic skeleton.
  • present invention relates to the synthesis of new ⁇ -carbolinics derivatives useful for the treatment of metabolic syndrome and, particularly to the treatment of diabetes, which show improved therapeutically activity in comparison with similar compounds existing in the prior art, even at lower doses.
  • the metabolic syndrome represents a collection of factors, such as hypertension, obesity, hyperlipidemia and diabetes (3), among others, associated with increased risk for cardiovascular disease. Metabolic syndrome is becoming increasingly common, largely as a result of the increase in the prevalence of obesity (4). Although it is generally agreed that first-line clinical intervention for the metabolic syndrome is lifestyle change, this is insufficient to normalize the risk factors in many patients, and so residual risk could be high enough to justify drug therapy. There is growing interest in therapeutic strategies that might target multiple risk factors more effectively, thereby minimizing problems with polypharmacy (3, 4).
  • the invention comprises the compounds of general formula I and any pharmaceutically, cosmetically or food grade acceptable salt thereof:
  • R 1 can selected from: linear or cycled mono or dialkylamines; aminoalkylalcohols or aminoalkylethers;
  • R 2 can be selected from: benzene or heterocycle rings
  • R 3 can be selected from: H; a hydrocarbon radical selected from straight or branched alkyl of from 1 to 5 carbons; or benzyl group;
  • R 4 can be selected from: H; a hydrocarbon radical selected from straight or branched alkyl of from 1 to 5 carbons; hydroxy or alkoxy radicals; or halogen.
  • Preferred compounds according to general formula I are those that, independently,
  • R 1 when being a linear alkylamine is selected from: NH—(CH 2 ) n —NH 2 ; NH—(CH 2 ) n —R 6 , being n a value between 0 and 4; NH—N ⁇ CH-phenyl-R 7 ;
  • R 1 when being a cycled amine is selected from:
  • R 1 when being an aminoalkylalcohol group is HNCH 2 CH 2 OH; and when being an aminoalkylether group is HNCH 2 CH 2 OCH 3
  • R 2 when being a benzene substituted ring is selected from:
  • R 4 when being a halogen is fluorine
  • R 5 can be selected from: H; alkoxy; halogen; hydroxy; or halogen-alkyl;
  • R 6 can be selected from: an alkyl, hydroxy or alkoxy moiety
  • R 7 can be selected from: H or NO 2 ;
  • R 8 can be selected from: H; hydroxy; alkoxy;
  • R 5 can be selected from: methoxy; chlorine, OH or trifluormethyl, preferably, when R 5 is H, R 8 is OH and when R 5 is OH, R 8 is OCH 3 .
  • Preferred compounds are those wherein, wherein R 6 is selected from: OH, ethyl or methoxy.
  • R 1 can selected from: OH, p-OCH 3 , NH—(CH 2 ) n —NH 2 being n a value between 0 and 3;
  • R 5 can be selected from: OCH 3 or H;
  • R 7 can be selected from: H or p-NO 2
  • preferred compounds are those wherein, when R 1 is a group OH, R 5 is selected from H or p-OCH 3 .
  • Still preferred compounds are those having a formula II selected from formula 1a wherein R 1 is a group OH and R 5 is p-OCH 3 ; or from formula 1b, wherein R 1 is a group OH and R 5 is H.
  • preferred compounds are those wherein, when R 1 is a group OCH 3 , R 5 is selected from H or p-OCH 3 .
  • Preferred compounds according to present invention are those having a formula II selected from: formula 2a, wherein R 1 is a group OCH 3 and R 5 is p-OCH 3 ; from formula 2b, wherein R 1 is a group OCH 3 and R 5 is H; or having a formula III selected from formula 3a, wherein R 1 is a group OCH 3 and R 5 is p-OCH 3 or from formula 3b, wherein R 1 is a group OCH 3 and R 5 is H.
  • Preferred compounds according to present invention are those having a formula III selected from formula 4a, wherein R 1 is NH(CH 2 ) 2 NH 2 and R 5 is p-OCH 3 ; or from formula 5a, wherein R 1 is NH(CH 2 ) 3 NH 2 and R 5 is p-OCH 3 .
  • Compounds also comprises in the present invention are those having a formula III selected from formula 6a, wherein R 1 is NHNH 2 and R 5 is p-OCH 3 ; or from formula 6b, wherein R 1 is NHNH 2 and R 5 is H.
  • preferred compounds are those wherein, in formula III, when being R 1 a group NH—N ⁇ CH-phenyl, R 5 is p-OCH 3 and when being R 1 a group NH—N ⁇ CH— phenyl substituted by a group p-NO 2 , R 5 is H.
  • Still most preferred compounds according to the present invention are selected among compounds: 4a, 5a, 7a, 17a, 17b, 17c, 21a, 21b, 21c, 21d, 21e, 21f, 23a, 23b, 23c, 23d, 23e, 23f, 26a or 26b, as shown in Table 1.
  • Present invention also covers all intermediate compounds in the synthesis of compounds of previously described compounds.
  • the invention covers intermediate compounds selected from: 1a, 1b, 2a, 2b, 3a, 3b, 6a, 6b, 7b, 8, 9, 13, 14a, 14b, 14c, 15a, 15b, 15c, 16a, 16b, 16c, 18a, 18b, 18c, 18d, 18e, 18f, 19a, 19b, 19c, 19d, 19e, 19f, 20a, 20b, 20c, 20d, 20e, 20f, 22a, 22b, 22c, 22d, 22e, 22f, 24a, 24b, 25a, or 25b.
  • the invention includes pharmaceutical, cosmetic, functional food additive or nutraceutical compositions comprising at least any of the previously mentioned compounds represented by general formulas I, II and III, and their pharmaceutically, cosmetically or food grade, acceptable or allowable, salts and combinations thereof, optionally with any inert ingredient, carrier, excipient or alike.
  • the invention also comprises any of the compounds covered by general formula I, II or III as previously disclosed or any pharmaceutical composition comprising the same, for use as medicament, or for use for manufacturing a medicament.
  • the invention also comprises any of the compounds covered by general formula I, II or III, as previously disclosed, or pharmaceutical compositions comprising the same, for use in the treatment or prevention of metabolic syndrome, metabolic disease or metabolic disorders, or for use in manufacturing a medicament for the treatment or prevention of metabolic syndrome, metabolic disease or metabolic disorders.
  • the invention also comprises compounds named as: 4a, 5a, 7a, 21a, 21b, 21e, 23a, 23b, 23d, 23e, 23f or 26b, taken alone or in combinations thereof, or pharmaceutical compositions comprising the same, are particularly suitable for use in the treatment or prevention of metabolic syndrome, or for use in manufacturing a medicament for the treatment or prevention of metabolic syndrome.
  • the invention also comprises any of the compounds covered by general formula I, II or III, as previously disclosed, or pharmaceutical compositions comprising the same, for use in the treatment or prevention of diabetes, or for use in manufacturing a medicament for the treatment or prevention of diabetes.
  • the invention also comprises compounds named as: 4a, 5a, 7a, 21a, 21b, 21e, 23a, 23b, 23d, 23e, 23f or 26b, taken alone or in combinations thereof, or pharmaceutical compositions comprising the same, are particularly suitable for use in the treatment or prevention of diabetes, or for use in manufacturing a medicament for the treatment or prevention of diabetes.
  • the invention also comprises any of the compounds covered by general formula I, II or III, as previously disclosed, for any pharmaceutical composition comprising the same, for use in the treatment or prevention of hypertension, or for use in manufacturing a medicament for the treatment or prevention of hypertension.
  • the invention also comprises compounds named as: 4a, 5a, 7a, 21a, 21b, 21e, 23a, 23b, 23d, 23e, 23f or 26b, taken alone or in combinations thereof, or any pharmaceutical composition comprising the same, are particularly suitable for use in the treatment or prevention of hypertension, or for use in manufacturing a medicament for the treatment or prevention of hypertension. More preferably, compounds 4a, 5a and 7a or any pharmaceutical composition comprising the same, are selected for use in the treatment or prevention of hypertension, or for use in manufacturing a medicament for the treatment or prevention of hypertension.
  • the invention also comprises any of the compounds covered by general formula I, II or III, as previously disclosed, or any pharmaceutical composition comprising the same, for use in the treatment or prevention of hyperlipidemia, assessed mainly as hypercholesterolemia, or for use in manufacturing a medicament for the treatment or prevention of hyperlipidemia, in general, and particularly for treatment or prevention of hypercholesterolemia.
  • the invention also comprises compounds named as: 4a, 5a, 7a, 21a, 21b, 21e, 23a, 23b, 23d, 23e, 23f or 26b, taken alone or in combinations thereof, or any pharmaceutical composition comprising the same, for use in the treatment or prevention of hyperlipidemia, assessed mainly as hypercholesterolemia, or for use in manufacturing a medicament for the treatment or prevention of hyperlipidemia, in general, and particularly for treatment or prevention of hypercholesterolemia.
  • compounds 4a, 5a and 7a or any pharmaceutical composition comprising the same are selected for use in the treatment or prevention of hyperlipidemia, assessed mainly as hypercholesterolemia, or for use in manufacturing a medicament for the treatment or prevention of hyperlipidemia, in general, and particularly for treatment or prevention of hypercholesterolemia.
  • the invention also comprises any of the compounds covered by general formula I, II or III, as previously disclosed, or any pharmaceutical composition comprising the same, for use in the treatment or prevention of hyperlipidemia, assessed mainly as hypertriglyceridemia, or for use in manufacturing a medicament for the treatment or prevention of hyperlipidemia, in general, and particularly for treatment or prevention of hypertriglyceridemia.
  • the invention also comprises compounds named as: 4a, 5a, 7a, 21a, 21b, 21e, 23a, 23b, 23d, 23e, 23f or 26b, taken alone or in combinations thereof, or any pharmaceutical composition comprising the same, are particularly suitable for use in the treatment or prevention of hyperlipidemia, assessed mainly as hypertriglyceridemia, or for use in manufacturing a medicament for the treatment or prevention of hyperlipidemia, in general, and particularly for treatment or prevention of hypertriglyceridemia.
  • compound 4a is selected for use in the treatment or prevention of hyperlipidemia, assessed mainly as hypertriglyceridemia, or for use in manufacturing a medicament for the treatment or prevention of hyperlipidemia, in general, and particularly for treatment or prevention of hypertriglyceridemia.
  • the invention also comprises any of the compounds covered by general formula I, II or III as previously disclosed, or any pharmaceutical composition comprising the same, for use in the treatment or prevention of obesity or overweight, or for use in manufacturing a medicament for the treatment or prevention of obesity or overweight.
  • the invention also comprises compounds named as: 4a, 5a, 7a, 21a, 21b, 21e, 23a, 23b, 23d, 23e, 23f or 26b, taken alone or in combinations thereof, or any pharmaceutical composition comprising the same, they all are particularly suitable for use in the treatment or prevention of obesity or overweight, or for use in manufacturing a medicament for the treatment or prevention of obesity or overweight. More preferably, compound 5a or any pharmaceutical composition comprising the same, it is selected for use in the treatment or prevention of obesity or overweight, or for use in manufacturing a medicament for the treatment or prevention of obesity or overweight.
  • the invention also comprises any of the compounds covered by general formula I, II or III as previously disclosed, or any cosmetic composition comprising the same, for use as cosmetic particularly for reducing obesity or overweight, or for use in manufacturing a cosmetic particularly for reducing obesity or overweight.
  • the invention also comprises compounds named as: 4a, 5a, 7a, 21a, 21b, 21e, 23a, 23b, 23d, 23e, 23f or 26b, taken alone or in combinations thereof, or any cosmetic composition comprising the same, they are particularly suitable for use as cosmetic particularly for reducing obesity or overweight, or for use in manufacturing a cosmetic particularly for reducing obesity or overweight. More preferably, compound 5a or any cosmetic composition comprising the same, it is selected for use as cosmetic particularly for reducing obesity or overweight, or for use in manufacturing a cosmetic particularly for reducing obesity or overweight.
  • the invention also comprises any of the compounds covered by general formula I, II or III as previously disclosed, or any functional food additive or nutraceutical composition comprising the same, for use as food functional additive or nutraceutic particularly for preventing or for reducing the symptoms related to: diabetes, elevated glucose blood levels, hypertension, elevated blood cholesterol levels, elevated blood triglycerides levels, obesity or overweight, or for use in manufacturing a food functional additive or nutraceutic particularly for preventing or for reducing the symptoms related to: diabetes, elevated glucose blood levels, hypertension, elevated blood cholesterol levels, elevated blood triglycerides levels, obesity or overweight.
  • the invention also comprises compounds named as: 4a, 5a, 7a, 21a, 21b, 21e, 23a, 23b, 23d, 23e, 23f or 26b, taken alone or in combinations thereof, or any functional food additive or nutraceutical composition comprising the same, they are particularly suitable for use as food functional additive or nutraceutic particularly for preventing or for reducing the symptoms related to: diabetes, elevated glucose blood levels, hypertension, elevated blood cholesterol levels, elevated blood triglycerides levels, obesity or overweight, or for use in manufacturing a food functional additive or nutraceutic particularly for preventing or for reducing the symptoms related to: diabetes, elevated glucose blood levels, hypertension, elevated blood cholesterol levels, elevated blood triglycerides levels, obesity or overweight.
  • the invention also discloses processes for producing the different compounds represented by formula I, II or III.
  • R 1 can selected from: linear or cycled mono or dialkylamines; aminoalkylalcohols or aminoalkylethers;
  • R 2 can be selected from: benzene or heterocycle rings
  • R 3 can be selected from: H; a hydrocarbon radical selected from straight or branched alkyl of from 1 to 5 carbons; or benzyl group;
  • R 4 can be selected from: H; a hydrocarbon radical selected from straight or branched alkyl of from 1 to 5 carbons; hydroxy or alkoxy radicals; or halogen, which comprises:
  • step iv) is replaced, alternatively, as follows:
  • step v) is replaced, alternatively, as follows:
  • the inventions also disclose the different processes for preparation of each one of the claimed compounds.
  • FIG. 1 Hypoglycemic effect of 3-(carbohydrazyl-N′-phenylsubstituted)-1-benzosubstituted- ⁇ -carbolinic-3-carbohydrazide (compound 7a or ANIS-BZ), just 1 (A) and 3 (B) days after being administered orally to experimental animals at 5 mg/kg dose compared to the increase of glycemia induced by the glucose overload in normal rats (control) and the glycemia reduction achieved with metformin (MET).
  • Each bar represents the mean ⁇ SEM of 6 animals. *P ⁇ 0.05, **P ⁇ 0.01, compared with vehicle-treated control group.
  • FIG. 2 Hypoglycemic effect after 3 days, of 3-(carbohydrazyl-N′-phenylsubstitute)-1-benzosubstitute- ⁇ -carbolinic-3-carbohydrazide (compound 7a or ANIS-BZ) at 0.5, 1 and 5 mg/kg doses compared to the increase of glycemia induced by glucose overload in normal rats and the glycemia reduction achieved with metformin (MET).
  • Each bar represents the mean ⁇ SEM of 6 animals. **P ⁇ 0.01, ***P ⁇ 0.001, compared with vehicle-treated control group.
  • FIG. 3 Hypoglycemic effect of N(-ethylamine)-1-benzosubstituted- ⁇ -carboline-3-carboxamide (compound 4a or ANIS-NH2), 1 (A) and 3 (B) days after being administered orally to experimental animals at 5 mg/kg dose compared to the increase of glycemia induced by the glucose overload in normal rats (control) and the glycemia reduction achieved with metformin (MET). Each bar represents the mean ⁇ SEM of 6 animals. *P ⁇ 0.05, **P ⁇ 0.01 compared with vehicle-treated control group.
  • FIG. 4 Hypoglycemic effect after 3 days, of N(-ethylamine)-1-benzosubstituted- ⁇ -carboline-3-carboxamide (compound 4a or ANIS-NH2) at 0.5, 1 and 5 mg/kg doses compared to the increase of glycemia induced by glucose overload in normal rats and the glycemia reduction achieved with metformin (MET).
  • Each bar represents the mean ⁇ SEM of 6 animals. **P ⁇ 0.01 compared with vehicle-treated control group.
  • FIG. 5 Plasma cholesterol levels in SHR hypertensive rats treated with 4a or 5a or 7a at doses of 5 mg/kg the first 4 days, 10 mg/kg during the next 4 days and 15 mg/Kg until the end of the treatment period (25 days) or with metformin (MET) (positive control dissolved in water at 300 mg/Kg) compared with plasma cholesterol levels of untreated SHR rats (vehicle or control).
  • MET metformin
  • FIG. 6 Plasma triglycerides levels in SHR hypertensive rats treated with 4a at doses of 5 mg/kg the first 4 days, 10 mg/kg during the next 4 days and 15 mg/Kg until the end of the treatment period (25 days) or with metformin (MET) (positive control dissolved in water at 300 mg/Kg) compared with plasma cholesterol levels of untreated SHR rats (vehicle or control).
  • MET metformin
  • Each bar represents the mean ⁇ SEM of 6 animals. *P ⁇ 0.05 compared with vehicle-treated control group.
  • FIG. 7 Hypoglycemic effect of compounds 23b or 21a; 3 days after being administered orally to experimental animals at 10 mg/kg doses compared to the increase of glycemia induced by the glucose overload in normal rats (vehicle-treated control group) and the glycemia reduction achieved with metformin (MET).
  • Each bar represents the mean of six animals and the vertical lines show the S.E.M. *P ⁇ 0.05; **P ⁇ 0.01; ***P ⁇ 0.001) compared with vehicle-treated control group.
  • FIG. 8 Hypoglycemic effect of compounds 21b, 21e, 23e, 23a, 23d or 26b; 5 days after being administered orally to experimental animals at 10 mg/kg doses compared to the increase of glycemia induced by the glucose overload in normal rats (vehicle-treated control group) and the glycemia reduction achieved with metformin (MET).
  • Each bar represents the mean of five-eight animals and the vertical lines show the S.E.M.
  • Asterisks denote the significance levels in comparison with the vehicle-treated control group (one-way ANOVA followed by Newman-Keuls test). (*p ⁇ 0.05; **p ⁇ 0.01, ***p ⁇ 0.001).
  • the term “metabolic syndrome” as used herein refers to a collection of factors (metabolic abnormalities), such as hypertension, obesity, hyperlipidemia, diabetes, central obesity, hyperglycemia, hypertension, and hepatic steatosis among others, associated with increased risk for cardiovascular disease. Metabolic syndrome is becoming increasingly common, largely as a result of the increase in the prevalence of obesity (4).
  • the International Diabetes Foundation definition of metabolic syndrome is central obesity (body mass index>30 kg/m 2 ) and two or more of: 1) triglycerides>150 mg/dL; 2) high density lipoprotein (HDL) ⁇ 40 mg/kL in males, ⁇ 50 mg/dL in females, or specific treatment for low HDL; 3) elevated blood pressure (BP), e.g., systolic BP>130 mm Hg or diastolic BP>85 mm Hg, or treatment for elevated BP, or previous diagnosis of elevated BP; and 4) fasting blood glucose >100 mg/dL or previous diagnosis of type 2 diabetes.
  • metabolic syndrome “metabolic disease” or “metabolic disorders” should be taken as sinonimus.
  • diabetes refers to group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced.
  • Type 1 diabetes results from the body's failure to produce insulin, and presently requires the person to inject insulin.
  • IDDM insulin-dependent diabetes mellitus
  • Type 2 diabetes T2D results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency.
  • NIDDM non-insulin-dependent diabetes mellitus
  • GD Gestational diabetes
  • hypolipidemia or hyperlipoproteinemia, or hyperlipidaemia refers to a condition of abnormally elevated levels of any or all lipids and/or lipoproteins in the blood.
  • hypocholesterolemia refers to the presence of high levels of cholesterol in the blood. It is closely related to the terms “hyperlipidemia” (elevated levels of lipids in the blood) and “hyperlipoproteinemia” (elevated levels of lipoproteins in the blood).
  • hypotriglyceridemia refers to a high level of all glycerides, including monoglycerides, diglycerides and triglycerides. It has been associated with cardiovascular diseases, i.e. atherosclerosis, even in the absence of hypercholesterolemia (high cholesterol levels).
  • hypertension or high blood pressure or arterial hypertension refers to a chronic medical condition in which the blood pressure in the arteries is elevated. This requires the heart to work harder than normal to circulate blood through the blood vessels. Normal blood pressure at rest is within the range of 100-140 mmHg systolic (top reading) and 60-90 mmHg diastolic (bottom reading). High blood pressure is said to be present if it is persistently at or above 140/90 mmHg. Hypertension is a major risk factor for stroke, myocardial infarction (heart attacks), heart failure, aneurysms of the arteries (e.g. aortic aneurysm), peripheral arterial disease and is a cause of chronic kidney disease. Even moderate elevation of arterial blood pressure is associated with a shortened life expectancy.
  • the term “obesity or central obesity” as used herein refers to a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems.
  • Body mass index (BMI) a measurement which compares weight and height, defines people as overweight (pre-obese) if their BMI is between 25 and 30 kg/m 2 , and obese when it is greater than 30 kg/m 2 .
  • the term “nutraceutical or nutraucetic food” refers to any substance that could be a food or a part of a food and provides medical or health benefits, including the prevention and treatment of a disease,
  • the compound 3a (2.0 mmol) with approximately 6.0 ml of ethylenediamine, was agitated at room temperature for 24 hours. After amine evaporation and recrystallization with methanol, it provided the 4a compound with an output of 55%.
  • the propylamine- ⁇ -carbolinic derivative (compound 5a) was obtained by the addition to the methyl- ⁇ -carbolinic-3-carboxilate derivative (compound 3a) (1.7 mmol) an equimolar amount of propylenediamine in CHCl 3 /MeOH 1:1 under reflux, for approximately 32 hours.
  • the reaction was monitored by thin layer chromatography. After evaporation of all chloroform and methanol, in a rotating evaporator, the product was recrystallized with methanol/acetone, obtaining an overall yield of 68%.
  • N-hydrazyl- ⁇ -carbolinic (1.0 mmol) derivatives either (compound 6a) or (compound 6b) in water (10 ml) 2 drops of concentrated sulfuric acid were added. The mixture was kept under agitation, at 65° C., until complete solubilization. Afterwards, 1.50 mmol of the respective aromatic aldehydes (benzaldehyde for compound 6a or p-nitrobenzaldehyde for compound 6b) in ethanol (10 ml) were added and the solution was kept in reflux for 24 hours.
  • the mixture was put in ice-bath and neutralized with a 10% sodium bicarbonate solution and the formed precipitate was filtered in a Buchner's funnel and recrystallized with methanol.
  • the products 7a and 7b were obtained with a yield ranging of 58 to 60%.
  • Yellow oil obtained (700 mg) was purified by column chromatography in silicagel ((Acetone ⁇ Acetone: EtOH 9:1) and after, treated with MTBE and concentrated to dryness (this treatment was repeated twice) affording the compound 22e (JHG-1117-8) as greenish solid (420 mg; LC-MS: 97%; Yield: 72%).
  • L-Tryptophan 50 g, 0.24 mol was suspended in methanol (100 mL). This suspension was cooled at 0° C. and SOCl 2 (21.5 mL, 0.29 mol) was added dropwise. After, the reaction mixture was heated to reflux for 2 hours. During this time the starting material was completely dissolved and the solution was dark. After 2 hours an aliquot was concentrated to dryness and analyzed by HPLC-MS and 1H-NMR checking that compound 6a was obtained and the starting material was disappeared.
  • compound 3a the previously obtained compound 2 (50.0 g, 0.148 mol) was suspended in a mixture of xilene (1800 mL) and S (23.68 g, 0.74 mol) was added. The mixture was refluxed for 22 hours. After this time the reaction was cooled at 4° C. and kept with agitation overnight. A light brown solid was obtained. This solid was washed with petroleum ether and checking by HPLC-MS and 1H-NMR. 39.11 g (yield: 79%) of compound 3a were obtained.
  • the compound 4a hydrochloride (4a HCl) was treated, at room temperature, with a 1.25M solution of HCl (g) in EtOH (0.43 mL, 0.54 mmol) and the initial solution turning to suspension after 5 hours of stirring. A white solid (57 mg of compound 4a HCl) was formed. It was filtered and washed with cool EtOH. To confirm whether the compound 4a HCl obtained is mono or dihydrochloride as would be necessary to perform elemental analysis for example: HPCL, LC-MS, etc. The obtained compound is soluble in water. Structure confirmed by NMR.
  • the glucose tolerance test is a reference method for the diagnosis of diabetes or glucose intolerance (5).
  • Distinct rat groups were orally treated, once a day, with 3-(carbohydrazyl-N′-phenylsubstituted)-1-benzosubstituted- ⁇ -carbolinic-3-carbohydrazide (compound 7a or ANIS-BZ) at doses: 0.5, 1 or 5 mg/kg or vehicle (control) for 3 days.
  • another rat group received metformin (reference drug used for lowering glucose serum levels) in a 300 mg/kg dose, orally, once a day for 3 days.
  • metformin reference drug used for lowering glucose serum levels
  • the oral glucose tolerance test was carried out by administering of a glucose solution (2 g/kg body mass). Glycemia was determined at zero time (before oral administering) and at 60 minutes after the glucose overload.
  • FIG. 1A shows that on the first day, the oral treatment with 3-(carbohydrazyl-N′-phenylsubstituted)-1-benzosubstituted- ⁇ -carbolinic-3-carbohydrazide (compound 7a or ANIS-BZ) in a 5 mg/kg dose, reduces the glycemic levels of animals that received an oral glucose overload when compared to the control group. Similarly, the oral treatment with metformin induces reduction of glycemic levels, but a doses 60 times fold higher.
  • FIG. 1B shows that after 3 days, the oral treatment with 3-(carbohydrazyl-N′-phenylsubstituted)-1-benzosubstituted- ⁇ -carbolinic-3-carbohydrazide (compound 7a or ANIS-BZ), at 5 mg/kg dose, reduces the glycemic levels of animals that received oral glucose overload when compared to the control group. Similarly, the oral treatment with metformin induces glycemic levels reduction but a doses 60 times fold higher.
  • compound 7a or ANIS-BZ 3-(carbohydrazyl-N′-phenylsubstituted)-1-benzosubstituted- ⁇ -carbolinic-3-carbohydrazide
  • FIG. 2 shows that after 3 days of oral treatment with 3-(carbohydrazil-N′-phenylsubstituted)-1-benzosubstituted- ⁇ -carbolinic-3-carbohydrazide (compound 7a or ANIS-BZ), only the 1 and 5 mg/kg doses reduced statistically significant the glycemic levels of animals that received oral glucose overload when compared to the control group. Similarly, the oral treatment with metformin induces reduction of glycemic levels, but a doses 60 times fold higher.
  • Distinct groups of rats were treated orally, once a day, with N(-ethylamine)-1-benzosubstituted- ⁇ -carboline-3-carboxamide (compound 4a or ANIS-NH2) at doses: 0.5, 1 or 5 mg/kg, or vehicle for 3 days.
  • another group of rats received metformin in a 300 mg/kg dose orally for 3 days once a day.
  • the oral glucose tolerance test was done under the administration of a glucose solution (2 g/kg body mass). Glycemia will be determined at the zero (before oral administration) time and 60 minutes after glucose overload.
  • FIG. 3A shows that on the first day, the oral treatment with N(-ethylamine)-1-benzosubstituted- ⁇ -carboline-3-carboxamide (compound 4a or ANIS-NH2) in a 5 mg/kg dose, reduces the glycemic levels of animals that received an oral glucose overload when compared to the control group. Similarly, the oral treatment with metformin induces reduction of glycemic levels, but a doses 60 times fold higher.
  • compound 4a or ANIS-NH2 N(-ethylamine)-1-benzosubstituted- ⁇ -carboline-3-carboxamide
  • FIG. 3B shows that after 3 days, the oral treatment with N(-ethylamine)-1-benzosubstituted- ⁇ -carboline-3-carboxamide (compound 4a or ANIS-NH2), at 5 mg/kg dose, reduces the glycemic levels of animals that received oral glucose overload when compared to the control group. Similarly, the oral treatment with metformin induces glycemic levels reduction but a doses 60 times fold higher.
  • compound 4a or ANIS-NH2 N(-ethylamine)-1-benzosubstituted- ⁇ -carboline-3-carboxamide
  • FIG. 4 shows that after 3 days of oral treatment with N(-ethylamine)-1-benzosubstituted- ⁇ -carboline-3-carboxamide (compound 4a or ANIS-NH2), only the 1 and 5 mg/kg doses reduced statistically significant the glycemic levels of animals that received oral glucose overload when compared to the control group. Similarly, the oral treatment with metformin induces reduction of glycemic levels, but a doses 60 times fold higher.
  • Distinct rat groups were orally treated, once a day, with 5 mg/kg of compounds 4a or 5a or 6a during the first 4 days, 10 mg/kg during the next 4 days and 15 mg/kg until the end of the treatment period or vehicle (control) for the same days.
  • another rat group received metformin (MET) (reference drug used for lowering glucose serum levels) in a 300 mg/kg dose, orally, from day 1 to the end of the treatment.
  • Plasma cholesterol levels were measured in triplicate 12 hours after drug administration by the cholesterol oxidase/peroxidase method (BioSystems S.A, Barcelona, Spain). Blood samples were obtained by femoral vein punction. This method was chosen because of its noninvasive character, enabling daily measurements with the same rats throughout the entire treatment.
  • Compounds 4a, 5a and in a less degree compound 7a, disclosed in the present invention shows in SHR rats an inhibitory effect on systolic blood pressure at different times and doses of treatment. This effect at 5-15 mg/kg is greater than that of metformin at 300 mg/kg.
  • Rats treated with compound 4a (p ⁇ 0.001), 5a (p ⁇ 0.001) and 7a (p ⁇ 0.05) decreased the systolic blood pressure between 5-7%, compared to the vehicle-control group, statistically significant.
  • Distinct rat groups were orally treated, once a day, with 5 mg/kg of compounds 4a or 5a or 6a during the first 4 days, 10 mg/kg during the next 4 days and 15 mg/kg until the end of the treatment period or vehicle (control) for the same days.
  • another rat group received metformin (reference drug used for lowering glucose serum levels) in a 300 mg/kg dose, orally, from day 1 to the end of the treatment.
  • Blood pressure was measured in triplicate 4 hours after drug administration in warmed warmed, restrained, conscious rats by the tail-cuff method with a computerized oscillometric system recorder (Nyprem, Cibertec). This method was chosen because of its noninvasive character, enabling daily measurements with the same rats throughout the entire treatment.
  • Compounds 4a, 5a and 7a, disclosed in the present invention shows, in SHR rats, inhibition of plasma cholesterol levels at 25 days of treatment (15 mg/Kg) similar to Metformin (300 mg/Kg) ( FIG. 5 ), although the latter did the effect at much higher concentration (20 times fold higher). This result indicates that said compounds are candidates to become medicaments to treat hypercholesterolemia or metabolic syndrome. The effect on plasma cholesterol levels was more pronounced for compounds 5a and 7a ( FIG. 5 ).
  • Distinct rat groups were orally treated, once a day, with 5 mg/kg of compound 4a during the first 4 days, 10 mg/kg during the next 4 days and 15 mg/kg until the end of the treatment period or vehicle (control) for the same days.
  • another rat group received metformin (reference drug used for lowering glucose serum levels) in a 300 mg/kg dose, orally, from day 1 to the end of the treatment.
  • Plasma triglyceride levels were measured in triplicate 12 hours after drug administration by the glycerol phosphate oxidase/peroxidase method (BioSystems S.A, Barcelona, Spain). Blood samples were obtained by femoral vein punction. This method was chosen because of its noninvasive character, enabling daily measurements with the same rats throughout the entire treatment.
  • Compound 4a disclosed in the present invention shows, in SHR rats a statistically significant (p ⁇ 0.05), inhibition of plasma triglyceride levels at 25 days of treatment (5-15 mg/Kg).
  • Distinct rat groups were orally treated, once a day, with 5 mg/kg of compound 5a during the first 4 days, 10 mg/kg during the next 4 days and 15 mg/kg until the end of the treatment period or vehicle (control) for the same days.
  • another rat group received metformin (reference drug used for lowering glucose serum levels) in a 300 mg/kg dose, orally, from day 1 to the end of the treatment.
  • Rats were weighted in a CHYO MK2000B precision weight chamber.
  • Compound 5a showed a statistically significant effect in lowering SHR body weight compared to control untreated rats (p ⁇ 0.05).
  • Distinct rat groups were orally treated, once a day, with 5 mg/kg of compound 4a during the first 4 days, 10 mg/kg during the next 4 days and 15 mg/kg until the end of the treatment period or vehicle (control) for the same days.
  • another rat group received metformin in a 300 mg/kg dose, orally, from day 1 to the end of the treatment.
  • Blood glucose levels were measured in triplicate 12 hours after drug administration with the aid of a GLUCOCARD TM G meter, GT-1810. Results were compared with the effect of metformin at the same dosis as the compounds. Blood samples were obtained by femoral vein punction. This method was chosen because of its noninvasive character, enabling daily measurements with the same rats throughout the entire treatment.
  • Compound 4a showed statistically significant (p ⁇ 0.01) blood glucose decrease in the range of doses from 5 to 15 mg/kg after treatment periods of 4-15 days between 5-7%, compared to the vehicle-control group. Metformin (300 mg/kg for 23 days) had a slightly greater effect on blood glucose levels, although the dose was much greater than that of the test compounds. Although SHR is not the best model to study glycemia, the results obtained were similar to those previously obtained in other animal model of diabetes, and suggest that the test compounds disclosed herein have a positive effect to regulate blood sugar levels.
  • Drosophila melanogaster (Oregon-R) flies were obtained by the University of the Balearic Islands (Spain). The larvae had access to food ad libitum during treatment. The larvae were seeded on standard food supplemented with the appropriate dose of compounds tested. Each compound was tested at 1, 10, 100, 1000 and 2000 ⁇ g/ml dissolved in standard food.
  • Drosophila melanogaster (Oregon-R strain) flies were maintained by serial transfers in 150 ml bottles containing 30 ml of yeast medium (water, agar, salt, sugar, and inactive yeast), complemented with a fungicide (methyl-4-hydroxybenzoate), antibacterial (propionic acid) and active yeast powder on the surface, at 25° C. and 65% humidity with day-night cycles. Fly adults were transferred from the serial transfer system to bottles with fresh food for 24 h. Adults 5 days old were placed on egg collecting devices (layers) containing a mixture of agar, water, acetic acid, and ethyl alcohol, with a drop of active yeast on it.
  • the layer glasses were changed, in this way, the eggs of a glass have similar age, with a maximum difference of 2 h. among them.
  • the glasses of the layers were kept at 25° C. for at least 22 h. in Petri dishes until larvae hatched. Fifty larvae were picked with a lancet under a stereoscopic microscope and were seeded into 10 ⁇ 2 cm vials with 5 ml food. Vials were supplemented with 4a, 5a and 7a at 1, 10 and 100 ⁇ g/ml.
  • As positive control we used cupric acetate (toxic) at 350 ⁇ g/ml.
  • the number of adult flies which emerged from each vial was counted daily until the exhaustion of the culture.
  • the parameters studied were the larvae-to-adult viability (V) and development time.
  • the data are expressed as the mean ⁇ SEM values from 3 independent experiments involving triplicate vials at the number of flies indicated.
  • the V and DT of the control larvae were approximately of 85% and 12 days, respectively.
  • the results showed that larvae-to-adult viability and development time were not affected by 4a, 5a and 7a compounds at the tested concentrations (Tables 6, 7 and 8). These results indicate a potential safety profile for these 4a, 5a and 7a compounds, at the doses assayed although, at least for compounds 5a and 7a, the safety profile may reach doses up to 2000 ⁇ g/mL.
  • mice Female Swiss mice (20-30 g), housed under a 12-h light-dark cycle, with controlled humidity (60-80%), and temperature (22 ⁇ 1° C.). Food and water were freely available to the mice.
  • the observations comprised the behavior and manifestations of the toxic symptoms, and were carried out according to the Guidelines of the Organization for Economic Cooperation and Development (OECD, 2008).
  • mice All compounds were dissolved in sterile saline and were administered by oral gavage to mice based in the weight, for example 20 g received 20 ⁇ L.
  • mice The oral (2000 mg/kg) administration of 4a, 5a or 7a compounds in mice did not produce mortality or any behavioral disorders, after observation for 14 days.
  • mice Male Wistar rats (200-300 g) were utilized provided by Mato Grosso do Sul's Federal University's Biotherium. Until the experiments were carried out, the animals have had free access to feed and water. The room temperature was kept at 22 ⁇ 2° C. with controlled humidity (60-80%) and the light/dark cycle was of 12 hours.
  • the glucose tolerance test was evaluated as described by Al-Awaki et al (6).
  • Rats were randomly divided into six groups of four animals that were control group that received only a solution of saline, compound 23b group (10 mg/kg), compound 21a group (10 mg/kg) and metformin 300 mg/kg group. Respective treatments were made orally and daily for five days.
  • the oral treatment with metformin induces reduction of glycemic levels, but a doses 30 times fold higher ( FIG. 11 ).
  • only compound 23b and metformin (but at doses 30 times fold higher) reduced the glucose levels in relation to control group.
  • the glucose tolerance test was evaluated as described by Al-Awaki et al (6).
  • the compounds 21b, 23a and 23d were diluted firstly in 20 ⁇ l of ethanol and after in 980 ⁇ l de saline.
  • Compounds 21e, 23e and 26b were dissolved in sterile saline and were administered by oral gavage to rats based in the weight, for example 200 g received 200 ⁇ L.
  • compounds 21b, 21e, 23e, 23d or 26b and metformin (but at a doses 30 times fold higher) reduced the glucose levels in relation to control group ( FIG. 8 ).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Birds (AREA)
  • Food Science & Technology (AREA)
  • Mycology (AREA)
  • Polymers & Plastics (AREA)
  • Nutrition Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Dermatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pediatric Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Cosmetics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US14/007,868 2011-03-28 2012-03-28 Compounds for treatment of metabolic syndrome Active US9440966B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/007,868 US9440966B2 (en) 2011-03-28 2012-03-28 Compounds for treatment of metabolic syndrome

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201161468163P 2011-03-28 2011-03-28
US14/007,868 US9440966B2 (en) 2011-03-28 2012-03-28 Compounds for treatment of metabolic syndrome
PCT/EP2012/055570 WO2012130912A1 (en) 2011-03-28 2012-03-28 Compounds for treatment of metabolic syndrome

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/055570 A-371-Of-International WO2012130912A1 (en) 2011-03-28 2012-03-28 Compounds for treatment of metabolic syndrome

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/136,277 Division US20160340355A1 (en) 2011-03-28 2016-04-22 Compounds for treatment of metabolic syndrome

Publications (2)

Publication Number Publication Date
US20150051204A1 US20150051204A1 (en) 2015-02-19
US9440966B2 true US9440966B2 (en) 2016-09-13

Family

ID=45974264

Family Applications (2)

Application Number Title Priority Date Filing Date
US14/007,868 Active US9440966B2 (en) 2011-03-28 2012-03-28 Compounds for treatment of metabolic syndrome
US15/136,277 Abandoned US20160340355A1 (en) 2011-03-28 2016-04-22 Compounds for treatment of metabolic syndrome

Family Applications After (1)

Application Number Title Priority Date Filing Date
US15/136,277 Abandoned US20160340355A1 (en) 2011-03-28 2016-04-22 Compounds for treatment of metabolic syndrome

Country Status (16)

Country Link
US (2) US9440966B2 (enrdf_load_stackoverflow)
EP (1) EP2691394B1 (enrdf_load_stackoverflow)
JP (1) JP6049216B2 (enrdf_load_stackoverflow)
KR (1) KR101784284B1 (enrdf_load_stackoverflow)
CN (2) CN103596949A (enrdf_load_stackoverflow)
AU (1) AU2012234230B2 (enrdf_load_stackoverflow)
BR (1) BR112013024602A2 (enrdf_load_stackoverflow)
CA (1) CA2831716C (enrdf_load_stackoverflow)
DK (1) DK2691394T3 (enrdf_load_stackoverflow)
ES (1) ES2635415T3 (enrdf_load_stackoverflow)
IL (1) IL228630A (enrdf_load_stackoverflow)
MX (1) MX349254B (enrdf_load_stackoverflow)
PL (1) PL2691394T3 (enrdf_load_stackoverflow)
PT (1) PT2691394T (enrdf_load_stackoverflow)
RU (1) RU2615136C2 (enrdf_load_stackoverflow)
WO (1) WO2012130912A1 (enrdf_load_stackoverflow)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106317180B (zh) * 2015-06-24 2019-09-13 首都医科大学 β-咔啉-3-甲酰-Orn-AA-NHCH2C6H5其合成，活性和应用
WO2018142379A1 (en) * 2017-02-06 2018-08-09 Joslin Diabetes Center, Inc. Methods and compositions for treating metabolic disorders
DK3595660T3 (da) 2017-03-14 2023-09-18 Sjt Molecular Res Sl Forbindelse til anvendelse i forebyggelse og/eller behandling af ikke-alkoholisk fedtleversygdom og ikke-alkoholisk steatohepatitis.
CN109134460B (zh) * 2018-08-02 2021-04-06 南开大学 一种β-咔啉类化合物的合成方法
CN109666615B (zh) 2019-02-20 2021-03-19 无限极（中国）有限公司 一种益生菌组合物及其应用
CN109628358B (zh) 2019-02-20 2021-03-19 无限极（中国）有限公司 一种复合益生菌及其应用
CN110585202A (zh) * 2019-10-27 2019-12-20 淮安市厚沐医疗技术咨询中心 一种β-咔啉生物碱及其葡萄糖苷用于抑制肝脏糖异生的用途
WO2021195603A1 (en) * 2020-03-27 2021-09-30 Virginia Polytechnic Institute And State University Anti-malarial compounds and uses thereof
CN112047940B (zh) * 2020-08-28 2021-06-29 南通大学 含1-(3,4-二甲氧基苯基)-β-咔啉单元的吡唑化合物的制备与用途
CN111892596B (zh) * 2020-08-28 2022-07-15 南通大学 含多氟吡唑结构的β-咔啉类化合物的制备和应用
CN116675689A (zh) * 2023-05-05 2023-09-01 五邑大学 一种β-咔啉类衍生物及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE612725A (fr) 1961-01-18 1962-07-17 Geigy Ag J R Nouveaux dérivés de la beta-carboline porteurs d'une fonction amide et leur préparation
US20100087415A1 (en) 2008-10-03 2010-04-08 Calcimedica, Inc. Inhibitors of store operated calcium release
US20100173931A1 (en) 2009-01-06 2010-07-08 Osteogenex Inc. Harmine derivatives for reducing body weight

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064420A1 (en) * 1998-06-12 1999-12-16 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S β-CARBOLINE COMPOUNDS
RU2271350C2 (ru) * 2000-06-09 2006-03-10 Санофи-Авентис Дойчланд Гмбх Производные ацилфенилмочевины, фармацевтическая композиция и способ ее получения
CN1802375A (zh) * 2003-04-09 2006-07-12 千禧药品公司 用于治疗炎性疾病的β－咔啉
WO2008103470A2 (en) * 2007-02-21 2008-08-28 Trustees Of Columbia University In The City Of New York Oncogenic-ras-signal dependent lethal compounds
EP2033962A1 (en) * 2007-08-22 2009-03-11 4Sc Ag Tetracyclic indolopyridines as EG5 inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE612725A (fr) 1961-01-18 1962-07-17 Geigy Ag J R Nouveaux dérivés de la beta-carboline porteurs d'une fonction amide et leur préparation
GB975835A (en) 1961-01-18 1964-11-18 Geigy Ag J R Process for the preparation of new ª‰-carboline-carboxylic acid amide derivatives
US20100087415A1 (en) 2008-10-03 2010-04-08 Calcimedica, Inc. Inhibitors of store operated calcium release
US20100173931A1 (en) 2009-01-06 2010-07-08 Osteogenex Inc. Harmine derivatives for reducing body weight
WO2010080756A2 (en) 2009-01-06 2010-07-15 Osteogenex, Inc. Harmine derivatives for reducing body weight

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
Abdel-Moty, SG, et al.; "Synthesis of cytotoxic 1-polyhydroxyalkyl-Beta-carboline derivatives," European Journal of Medicinal Chemistry, 1997, pp. 1009-1017, vol. 32.
Al-Awadi, F.M., et al.; "On the mechanism of the hypoglycaemic effect of a plant extract," Diabetologia, 1985, pp. 432-434, vol. 28.
Cai, Wen, et al.; "Synthesis, methabolism and in vitro cytotoxicity studies on novel lavendamycin antitumor agents," Bioorganic & Medicinal Chemistry, 2010, pp. 1899-1909, vol. 18.
Crunkhorn, Sarah; "Birch bark compound combats metabolic syndrome," Nature Reviews, Drug Discovery 2011, p. 172, vol. 10.
Database CA [Online]; Chemical Abstracts Service, Zhang, Jing Xin et al.: "Solid phase synthesis of .beta.-carbolines," XP002678192; Database accession No. 2000:825550.
Düsman Tonin, Lilian T., et al.; "Antitrypanosomal and antileishmanial activities of novel N-alkyl0(1-phenylsubstituted-Beta-carboline)-3-carboxamides," Biomedicine & Pharmacotherapy, 2010, pp. 386-389, vol. 64.
Gross, Jorge L., et al.; "Diabetes Mellitus: Diagnosis, Classification and Glucose Control Evaluation," Arq Bras Endocrinol Metab, 2002, pp. 16-26, vol. 46; and English Abstract.
Grundy, Scott M.; "Drug therapy of the metabolic syndrome: minimizing the emerging crisis in polypharmacy," Nature Review, Drug Discovery, 2006, pp. 295-309, vol. 5.
International Search Report, Jul. 3, 2012.
Molina, Pedro, et al.; "Inninophosphorane-Mediated Syntheses of the Fascaplysin Alkaloid of Marine Origin and Nitramarine," Tetrahedron Letters, 1994, pp. 8851-8854, vol. 35.
Nazari Formagio, Anelise S., et al.; "Synthesis and antiviral activity of beta-carboline derivatives bearing a substituted carbohydrazide at C-3 against poliovirus and herpes simples virus (HSV-1)," European Journal of Medicinal Chemistry, 2009, pp. 4695-4701, vol. 44.
Nazari Formagio, Anelise S., et al.; Synthesis and antitumoral activity of novel 3-(2-substituted-1,3,4-oxadiazol-5-yl) and 3-(5-substituted-1,2,4-triazol-3-yl) beta-carboline derivaties, Bioorganic & Medicinal Chemistry, 2008, pp. 9660-9667, vol. 16.
Panarese, Joseph D., et al.; "Room-Temperature Aromatization of Tetrahydro-Beta-carbolines by 2-lodoxybenzoic Acid: Utility in a Total Synthesis of Eudistomin U," Organic Letters, 2010, pp. 4086-4089, vol. 12.
Srivastava, Sanjay K., et al.; "Potent 1,3-Disubstituted-9 H-pyrido[3,4-b]indoles as New Lead Compounds in Antifilarial Chemotherapy," Bioorganic & Medicinal Chemistry, 1999, pp. 1223-1236, vol. 7.
Trinder, P.; "Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen," J. of Clin. Path.,1969, pp. 158-161, vol. 22.

Also Published As

Publication number Publication date
BR112013024602A2 (pt) 2020-10-13
KR20140025401A (ko) 2014-03-04
WO2012130912A1 (en) 2012-10-04
JP2014510741A (ja) 2014-05-01
RU2013147629A (ru) 2015-05-10
DK2691394T3 (en) 2017-08-28
AU2012234230A1 (en) 2013-10-17
RU2615136C2 (ru) 2017-04-04
KR101784284B1 (ko) 2017-10-11
IL228630A (en) 2017-03-30
PT2691394T (pt) 2017-08-14
MX349254B (es) 2017-07-19
EP2691394A1 (en) 2014-02-05
JP6049216B2 (ja) 2016-12-21
PL2691394T3 (pl) 2017-10-31
EP2691394B1 (en) 2017-05-10
CA2831716C (en) 2018-06-12
ES2635415T3 (es) 2017-10-03
US20160340355A1 (en) 2016-11-24
CA2831716A1 (en) 2012-10-04
MX2013011124A (es) 2014-03-31
AU2012234230B2 (en) 2016-12-01
CN107652283A (zh) 2018-02-02
IL228630A0 (en) 2013-12-31
CN103596949A (zh) 2014-02-19
CN107652283B (zh) 2021-07-06
US20150051204A1 (en) 2015-02-19

Similar Documents

Publication Publication Date Title
US9440966B2 (en) Compounds for treatment of metabolic syndrome
US10570156B2 (en) Substituted imidazo[1,2-a]pyridines as PDE-10 inhibitors
US5276058A (en) 3,4-dihydroxychalcone derivatives
US20120302533A1 (en) Derivatives of pyrimido [6,1-a] isoquinolin-4-one
FR2555584A1 (fr) Derives de l'acide fluoro-6-dihydro-1,4-oxo-4-piperazinyl substitue-7-quinoline-carboxylique-3 et procede pour leur preparation et compositions pharmaceutiques a action anti-bacteriennes a base desdits derives
NO161802B (no) Analogifremgangsmaate for fremstilling av terapeutisk aktive furo-(3,4-c)-pyridinderivater.
FI66868C (fi) Foerfarande foer framstaellning av imidazo(1,2-a)kinoxalinmetanoler anvaendbara saosom laekemedel
US11007186B2 (en) Methods of treating RBP4 related diseases with triazolopyridines
US12364693B2 (en) Methods of treating metabolic diseases with fused bicyclic pyrazoles
JP2020520949A (ja) 組成物、並びにミトコンドリア脱共役剤を調製及び使用する方法
US4179563A (en) 3-Aryloxy-substituted-aminopyridines and methods for their production
JPS6026388B2 (ja) ２−ヒドロキシメチル−３，４，５−トリヒドロキシ−ピペリジン誘導体、その製法及び利用
Lipinski et al. Bronchodilator and antiulcer phenoxypyrimidinones
US5124328A (en) Morpholine derivatives compositions and use
Ikhtiarudin et al. Microwave-assisted synthesis and in vivo anti-diabetic activity of 5-(2-bromophenyl)-3-(naphthalen-1-yl)-4, 5-dihydro-1H-pyrazole
JPH01279864A (ja) 新規の１，２―ジヒドロピリド〔３，４―ｂ〕―ピラジン類製造用の中間体
US12145936B1 (en) 7-Imino-5-(1H-indol-3-yl)-1,3-substituted-7,8-dihdropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione as anti-inflammatory agents
CN110305087B (zh) 一种5,6-二甲氧基茚酮化合物及其制备方法和用途
CN108558843B (zh) 一种香豆素-三唑-靛红型化合物及其制备方法和应用
CN116082239A (zh) Pde4/7双靶点抑制剂及其制备方法与应用
NO763233L (no) Fremgangsm}te for fremstilling av et nitrokumarin.

Legal Events

Date Code Title Description
AS Assignment

Owner name: SJT MOLECULAR RESEARCH, S.L., SPAIN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:AGREDA NAVAJAS, JUAN CARLOS;MIKIO KASSUYA, ROBERTO;SIGNING DATES FROM 20131015 TO 20131029;REEL/FRAME:031683/0798

STCF Information on status: patent grant

Free format text: PATENTED CASE

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2551); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

Year of fee payment: 4

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2552); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

Year of fee payment: 8